Catalytic Regioselective Olefin Hydroarylation(alkenylation) by Sequential Carbonickelation-Hydride Transfer

Article abstract of DOI:10.1021/jacs.1c03228

Alkene hydrocarbofunctionalization represents one of the most important classes of chemical transformations, but related branched-selective examples with unactivated olefins are scarce. Here, we report that catalytic amounts of a dimeric Ni(I) complex and an exogenous alkoxide base promote Markovnikov-selective hydroarylation(alkenylation) of unactivated and activated olefins using organo bromides or triflates derived from widely available phenols and ketones. Products bearing aryl- and alkenyl-substituted tertiary and quaternary centers could be isolated in up to 95% yield and >99:1 regioisomeric ratios. Contrary to previous dual-catalytic methods that rely on metal-hydride atom transfer (MHAT) to the olefin prior to carbofunctionalization with a cocatalyst, our mechanistic evidence points toward a nonradical reaction pathway that begins with site-selective carbonickelation across the C═C bond followed by hydride transfer using alkoxide as the hydride source. Utility of the single-catalyst protocol is highlighted through the synthesis of medicinally relevant scaffolds.

Full text of DOI:10.1021/jacs.1c03228

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Catalytic Regioselective Olefin Hydroarylation(alkenylation) by
Sequential Carbonickelation-Hydride Transfer
Chen-Fei Liu, Xiaohua Luo, Hongyu Wang,* and Ming Joo Koh*
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ABSTRACT: Alkene hydrocarbofunctionalization represents one
of the most important classes of chemical transformations, but
related branched-selective examples with unactivated olefins are
scarce. Here, we report that catalytic amounts of a dimeric Ni(I)
complex and an exogenous alkoxide base promote Markovnikov-
selective hydroarylation(alkenylation) of unactivated and activated
olefins using organo bromides or triflates derived from widely
available phenols and ketones. Products bearing aryl- and alkenyl-
substituted tertiary and quaternary centers could be isolated in up
to 95% yield and >99:1 regioisomeric ratios. Contrary to previous
dual-catalytic methods that rely on metal-hydride atom transfer (MHAT) to the olefin prior to carbofunctionalization with a
cocatalyst, our mechanistic evidence points toward a nonradical reaction pathway that begins with site-selective carbonickelation
across the CC bond followed by hydride transfer using alkoxide as the hydride source. Utility of the single-catalyst protocol is
highlighted through the synthesis of medicinally relevant scaffolds.
(Scheme 1b). We surmised that under appropriate conditions,
a single Ni-based complex should be capable of promoting
oxidative insertion with an sp2-hybridized electrophile to afford
an organonickel species that undergoes catalyst-controlled
Markovnikov-selective carbonickelation across an olefin. At
this stage, ligand substitution involving the alkylnickel
intermediate I with a judiciously selected hydride donor
should give rise to a Ni-hydride species II that is prone to
reductive elimination to deliver the desired branched product.
Such a catalytic regime, which has yet to be conceived to the
best of our knowledge, would be highly attractive for a number
of reasons (Scheme 1B, inset): (a) Rather than relying on two-
catalyst systems,29,30,36,37 only a single catalyst is necessary to
promote the reductive Heck reaction; (b) the method obviates
the intermediacy of radical species, which may otherwise
engender complications with radical traps29,38 and certain
substrates (e.g., vinylcyclopropanes29 and 1,6-dienes29); (c)
the inverse order of carbofunctionalization followed by hydride
transfer (vs conventionally established hydride transfer
carbofunctionalization) means that functionalized alkylnickel
intermediates that may be prone to isomerization1,39 can be
avoided. Overall, we believe the newly conceived strategy
INTRODUCTION
■
The ability to simultaneously generate C−C and C−H bonds
in a site-selective manner through insertions across carbon−
carbon π-bonds, without relying on substrate activation1−5
and/or strategically installed directing groups,6−9 is a sought-
after goal in catalytic alkene hydrocarbofunctionalization.10−12
In this field, considerable efforts have been devoted to the
development of metal-catalyzed hydroarylation reactions of
unactivated aliphatic CC bonds13−28 that deliver valuable
products with aryl- and heteroaryl-substituted carbon centers.
To date, a number of reports in intermolecular linear (anti-
Markovnikov)-selective transformations using arenes,14−16 aryl
nucleophiles,19−21,23−26 or electrophiles17,18,22 have been
disclosed. By comparison, the arguably more compelling
branched (Markovnikov)-selective variants,27,28 which can
furnish entities containing tertiary or quaternary stereogenic
centers, are discernibly less established.
State-of-the-art advances from Shenvi and co-workers29,30
take advantage of dual-catalytic systems (Co/Ni or Fe/Ni) in
the presence of a hydrosilane as hydride donor to promote
Co(Fe)-hydride atom transfer (or MHAT)31,32 to the alkene
substrate (Scheme 1a). Either the resulting radical cage
pair31,32 collapses to form an organometallic complex, or
cage escape occurs to yield a free radical. Following reaction
with an in situ-generated arylnickel species (derived from
oxidation addition of aryl iodide with the Ni-based cocatalyst)
and reductive elimination, the final hydroarylation adduct is
obtained (Scheme 1a, inset). Our interest in Ni-catalyzed
alkene functionalizations33−35 led us to conceptualize a new
reaction manifold that reverses the sequence of addition
Received: March 26, 2021
Published: June 21, 2021
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© 2021 American Chemical Society
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Scheme 1. Motivation for Developing Markovnikov-Selective Alkene Hydrocarbofunctionalization
would offer complementarity in scope to MHAT-induced
hydrocarbofunctionalizations11 for applications in organic
synthesis. Herein, we disclose the first cases of a Ni-catalyzed
olefin arylation(alkenylation)-hydride transfer protocol using
electrophilic organotriflate/bromide reagents (Scheme 1c).
1 (Table 1, entries 1−3). No reaction was observed when IPr-
derived Ni(II) complex Ni-241 was employed (Table 1, entry
6). In stark contrast, 71% GC yield of 3 (98:2 regioisomeric
ratio) was obtained when Ni-2 was replaced with 5 mol % of
the dimeric Ni(I) complex Ni-142 (Table 1, entry 7), although
appreciable amounts of 4 were still detected. In order to
suppress undesired Heck-type processes, we reasoned that an
alternative metal alkoxide that could more efficiently generate
the requisite Ni-hydride species II would reduce adventitious
β-H elimination and/or olefin isomerization43,44 within I (cf.
Scheme 1b). In the event, NaOi-Pr was identified as the
optimal hydride donor after a survey of various alkoxide bases
(Table 1, entries 8−11), affording 3 in 90% isolated yield and
97% branched selectivity with remarkably diminished 4 (Table
1, entry 11). As expected, <5% hydroarylation was observed
with NaOt-Bu (Table 1, entry 11), since the absence of a Cβ−
H bond in the corresponding Ni-tert-butoxide intermediate
precludes β-H elimination and hence Ni-hydride generation.
It merits mentioning that other commonly reported hydride
sources (alcohol,20,22,24,45,46 hydrosilane17,18,22) were ineffi-
cient in promoting hydroarylation under the Ni-catalyzed
conditions (Table 1, entries 12 and 13). Notably, lowering the
RESULTS AND DISCUSSION
■
Optimization Studies. We began by examining conditions
that merge unactivated alkene 1 (1 equiv) with phenyl triflate
2 (3 equiv) in the presence of a hydride donor (4 equiv) and
toluene as solvent at 40 °C. Using KOEt as the hydride source
(formation of Ni-hydride by β-H elimination of an in situ-
generated Ni-alkoxide species40), only 10 mol % of the Ni
complex derived from Ni(cod)2 and N-heterocyclic carbenes
(NHC) ligands (Table 1, entries 4 and 5) were capable of
promoting hydroarylation, with the more sizable L8 (IPr)
furnishing the desired 3 in 33% GC yield and 97% branched
selectivity (C-2:other regioisomers). However, significant
quantities of undesired Heck-type products 4 were also
detected (54:46 3:4). Other classes of ligands (bipyridine,
bisphosphine, bisoxazoline, and bioxazoline) were found to be
less effective and only afforded olefin isomerization products of
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substrates,30 aryl olefins and 1,3-dienes participated efficiently
in our reaction system, delivering the adducts 22−24 in up to
86% yield and 93:7−96:4 regioisomeric ratios. The site-
selective 1,2-addition to alkyl-substituted 1,3-diene to generate
branched product 24 is remarkable, since previous reports
documented inherent complications of allyl rearrangement,
leading to isomeric product mixtures (1,2- and 1,4-additions).1
Given that 1,6-dienes were susceptible to radical-based
cyclization in previously disclosed hydroarylation processes,29
we subjected an analogous substrate to our Ni-1-catalyzed
conditions and found that 25 could be obtained in 41% yield
and 94:6 regioselectivity with no trace of ring-closing. This
result provides support for the nonradical nature of our
hydrocarbofunctionalization transformation (see Scheme 5 for
more details). The formation of 26 shows that alkenes derived
from bioactive molecules are compatible under the hydro-
arylation conditions.
Hydro-aryl additions across 1,1-disubstituted CC bonds
were similarly efficient, furnishing 27−42 in up to 88% yield
and >99:1 branched selectivity (Scheme 3). Products with
sterically encumbered quaternary all-carbon centers that are
acyclic (27−29, 33−37, 39) or embedded within a ring system
(30−32, 38), as well as those with Si-substituted centers (40)
or derived from complex molecules (41, 42), could be
generated. Cyclopropane-functionalized 35 was obtained with
no trace of ring rupture29 (see Scheme 5 for more details).
Intriguingly, the reactions that delivered pharmaceutically
relevant piperidines47 31 and 32 (78−88% yield, 98:2 r.r.)
are somewhat higher-yielding and more selective compared to
dual-catalytic systems that afforded analogous products (∼60%
yield, 88:12−92:8 r.r.).28 1,2-Disubstituted olefins also served
as effective hydroarylation substrates to give synthetically
valuable heterocyclic building blocks 43 and 44. However,
trisubstituted olefins were inefficient under our reaction
conditions (<5% conversion to hydroarylation product).
As shown in Scheme 4a, the present catalytic method is
compatible with a wide array of functionalized aryl triflates
bearing electron-rich or electron-deficient groups on the ortho-,
meta-, and/or para-positions (noncommercial aryl triflates are
typically prepared in one step from readily available phenols).
Products 46−55 were isolated in 68−91% yield and ≥90%
Markovnikov selectivity. Synthesis of 56 demonstrates that
Lewis basic pyridine units are tolerated. Hydroalkenylation can
also be accomplished with alkenyl triflates which are derived
from the corresponding ketones (cyclic and acyclic), another
abundant class of feedstock chemicals. Regioselectivity was
high across the board, and 57−60 were formed in 34−81%
yield. It merits mention that access to these adducts using the
corresponding alkenyl halides constitutes a less practical
option, since synthesis of the haloalkene reagents is nontrivial.
Besides triflates, aryl and heteroaryl bromides were amenable
substrates under the standard conditions, furnishing 61−64 in
43−67% yield and up to 96% branched selectivity.
Table 1. Evaluation of Reaction Conditions
yield of 3 r.r. of
a
a
a
entry
1
Ni complex
hydride source
KOEt
(%)
3
3:4
Ni(cod)2 (10 mol %),
ND
NA
NA
NA
-
NA
L1 or L2 (12 mol %)
2
3
Ni(cod)2 (10 mol %),
L3 or L4 (12 mol %)
KOEt
KOEt
KOEt
KOEt
ND
ND
10
NA
NA
-
Ni(cod)2 (10 mol %),
L5 or L6 (12 mol %)
b
4
Ni(cod)2 (10 mol %),
L7 (25 mol %)
5
Ni(cod)2 (10 mol %),
33
97:3
54:46
L8 (25 mol %)
6
7
8
9
Ni-2 (10 mol %)
Ni-1 (5 mol %)
Ni-1 (5 mol %)
Ni-1 (5 mol %)
KOEt
ND
71
NA
NA
KOEt
98:2
98:2
95:5
83:17
39:61
95:5
NaOMe
23
NaOCH(Me)
Ph
81
10
11
12
13
Ni-1 (5 mol %)
Ni-1 (5 mol %)
Ni-1 (5 mol %)
Ni-1 (5 mol %)
NaOi-Pr
95 (90)
4
97:3
NA
NA
NA
97:3
6:94
NA
NaOt-Bu
BnOH, K3PO4
Et3SiH
ND
ND
NA
a
Yields, regioisomeric ratios (r.r.; C-2 (branched):other isomers), and
3:4 ratios were determined by GC analysis. Value in parentheses
b
denotes isolated yield. Product ratios were not determined. cod, 1,5-
cyclooctadiene; Bn, benzyl; IPr, 1,3-bis(2,6-diisopropylphenyl)-
imidazol-2-ylidene; ND, not detected; NA, not applicable.
alkoxide loading led to a noticeable increase in Heck-type side
product formation (see Scheme 5 for further discussion). In
addition, conducting the reductive Heck reaction with other
aryl electrophiles, such as halides, sulfonates, and diazonium
salts, or changing the reaction temperature gave inferior results
in efficiency and/or selectivity (see Supporting Information
(SI) Tables S1−S3 for details).
Substrate Scope and Synthetic Applications. We
proceeded to evaluate the scope of alkenes under our
established Ni-catalyzed conditions (Schemes 2 and 3).
Unactivated monosubstituted olefins containing diverse func-
tional groups are tolerated, affording the corresponding
hydroarylation products 5−17 in 67−92% yield and up to
98% Markovnikov selectivity (Scheme 2). These include
compounds that bear an ether (5, 13, 15), a silane (8), an
amino ester (9), an amide (14), a phthalimide (16), and
heterocyclic motifs (6, 17). Electron-rich olefins such as vinyl
enol ether and vinyl carbazole were also competent substrates,
delivering 18 and 19 with O- and N-substituted tertiary
centers, respectively. Additions to sterically congested α-
branched CC bonds could be achieved to give 20 and 21 in
78−93% yield and ≥96:4 branched selectivity.
Our single-catalyst hydrocarbofunctionalization strategy
offers the opportunity to design more concise synthetic routes
for the construction of biologically important compounds of
interest (Scheme 4b). In one instance, allyl addition to
commercially available ketone 65 followed by deoxyfluorina-
tion delivered alkene 67, which was treated with phenyl triflate
under our Ni-catalyzed conditions to furnish 68, a key
precursor to 5HT1D receptor ligand 69.48,49 Overall, the
synthesis of 68 was achieved in 45% yield over three steps,
In contrast to MHAT-mediated hydroarylation regimes
where activated alkenes such as styrenes were ineffective
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a
Scheme 2. Scope of Monosubstituted Olefins in Alkene Hydrocarbofunctionalization
a
b
Yields, regioisomeric ratios (r.r.; branched:other isomers), and diastereomeric ratios were determined by GC and 1H NMR analysis. The reaction
was conducted at 60 °C with 10 mol % Ni-1 and NaOi-Pr (5 equiv). See SI for details.
which compares favorably with a previous four-step synthesis
(12% overall yield).48,49
to elucidate the source that is responsible for delivering the
hydride (Scheme 5a). In the presence of 4 equiv of deuterated
NaOi-Pr (NaOC(D)Me2), the reaction between alkene 1 and
triflate 74 under the standard hydroarylation conditions
furnished the expected product d-11 in 72% yield (99:1 r.r.)
with ∼1.0 deuterium incorporation at the methyl terminus.
Similarly, subjecting cyclic alkene 75 to deuteroarylation gave
d-44 in 51% yield as a single regio- and syn-diastereomer
(presumably from syn-arylnickelation followed by stereo-
retentive C−D bond-forming reductive elimination). In
another experiment, the reaction between 45 and 76 using
excess alkoxide 77 delivered 51 in 80% yield and 95:5
branched selectivity, along with stoichiometric amounts of
ketone 78 (likely derived from dehydrogenation of 77) and
anisole 79 (likely generated by hydro-detriflation). NaOi-Pr
was not employed due to the difficulty of detecting the
In another formal synthesis of a narcotic agonist, subjecting
alkene 71 (derived from commercially available ketone 70) to
standard hydroarylation with 3-methoxyphenyl triflate fol-
lowed by HBr treatment furnished the desired piperidine
hydrobromide salt 72 in 98:2 r.r. as a single diastereomer.
Notably, the three-step generation of 72 (76% overall yield
from 70) is shorter and more efficient compared to previous
procedures.50 By coupling with different aryl triflates, the
present sequence also enables easy access to diverse analogues
within the family of narcotic agonists 73.50
Mechanistic Investigations. We carried out studies to
gain insights into the mechanistic underpinnings of our
developed Ni-1-catalyzed hydrocarbofunctionalization reac-
tions (Scheme 5). Specifically, experiments were conducted
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a
Scheme 3. Scope of 1,1- and 1,2-Disubstituted Olefins in Alkene Hydrocarbofunctionalization
a
b
Yields and regioisomeric ratios (r.r.; branched:other isomers) were determined by GC and 1H NMR analysis. The reaction was conducted with
10 mol % Ni-1, triflate (5 equiv), and NaOi-Pr (8 equiv). See SI for details.
corresponding low-molecular-weight acetone byproduct. These
results suggest that the hydride transferred to the alkene most
probably originates from the alkoxide base in the reaction
mixture.
increase in formation of undesired 83 (ratio of 11:83 = 92:8 →
61:39). This study intimates that a sufficient quantity of the
alkoxide is necessary to overcome adventitious Heck-type
processes and ensure efficient conversion of a putative Ni-
alkoxide to Ni-hydride for hydride transfer (see Scheme 6).
On the basis of our present observations, a plausible
nonradical mechanism for alkene hydrocarbofunctionalization
is illustrated in Scheme 6. Dissociation of the dimeric Ni-151
followed by chloride substitution by NaOi-Pr leads to a Ni(I)-
isopropoxide complex i. Oxidative insertion of the electrophile
85 (G = aryl, alkenyl) then affords Ni(III) species ii, which
undergoes a Markovnikov-selective carbonickelation across
alkene 84 to give Ni-alkyl complex iii. The observed
regioselectivity likely arises from reduced steric repulsions
between the sizable organonickel complex (larger compared to
G) and the olefinic substituents (R1 and R2) in the most
favored transition state.43,44 Contrary to previous reports in
which Ni-hydride addition precedes carbofunctionalization,52
it is noteworthy that carbonickelation appears to be favored
over any adventitious hydronickelation in our reaction system.
For alkenes where R1 or R2 is a hydrogen, an inherent
complication emerges: if NaOi-Pr is not present in adequate
amounts in solution, iii could potentially undergo intra-
Radical clock experiments were then performed to test the
intermediacy of radical species in our system (Scheme 5b).
The reaction of vinylcyclopropane 80 and 74 afforded the
corresponding hydroarylation adduct 81 in 67% yield (95:5
r.r., 56:44 d.r.), and no side products arising from ring-opening
were observed. As already highlighted in Scheme 2, hydro-
arylation of 1,6-diene 82 with 74 gave 25 in 41% yield and 94%
regioselectivity with <2% cyclization side products detected
(Scheme 5B). These observations are in contrast to MHAT-
dominated dual catalytic reactions, where cyclopropane ring
rupture and radical annulation were observed, respectively.28
To sum up, these investigations lend credence to the
proposition that long-lived radical intermediates are unlikely
to be involved, given that olefin carbonickelation precedes
hydride transfer (cf. Scheme 1B).
The requirement for excess alkoxide (hydride donor) in the
Ni-catalyzed manifold is corroborated in Scheme 5c. Lowering
the NaOi-Pr loading from 4 equiv to 1.5 equiv resulted in a
consequential diminution in the yield of 11 (92% → 40%) and
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a
Scheme 4. Scope of Electrophiles and Application to the Synthesis of Biologically Active Compounds
a
1
Yields, regioisomeric ratios (r.r.; branched:other isomers), and diastereomeric ratios were determined by GC and H NMR analysis. For the
synthesis of 46−60, triflates were employed. For the synthesis of 61−64, bromides were employed and the reaction was conducted with 10 mol %
b
c
Ni-1. The reaction was conducted on a 1 mmol scale. The reaction was conducted with 10 mol % Ni-1 and NaOi-Pr (5 equiv). See SI for details.
molecular β-H elimination to form Heck-type products,43,44
thereby competing with the desired hydrocarbo-
functionalization pathway. As described in Scheme 5C, any
undesired Heck-type reactions can be suppressed by ensuring
there is sufficient NaOi-Pr to induce conversion of iii to Ni-
bisalkoxide iv, so that dehydrogenation through β-H
elimination of the isopropoxide moiety predominates to
furnish Ni-hydride v with concomitant ejection of the acetone
byproduct. A final reductive elimination transfers the hydride
to generate 86 and turn over the catalytic cycle. Although the
poor reactivity and selectivity outcomes observed with the
corresponding Ni(0)- and Ni(II)-based precatalysts (cf. Table
1, entries 5 and 6 vs entry 7) suggest that an energetically
favorable Ni(I)/Ni(III)53 pathway may be dominant in our
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a
system, an alternative Ni(0)/Ni(II) cycle cannot be completely
excluded. Further studies are ongoing to fully verify these
intricate mechanistic details.
Scheme 5. Mechanistic Studies
CONCLUSIONS
■
By employing a reagent combination comprising a simple
alkoxide base and readily accessible organotriflates and
bromides, we demonstrate that a nonprecious NHC−Ni(I)
catalyst promotes Markovnikov-selective hydro-aryl(alkenyl)
additions to a diverse range of mono-, 1,1-, and 1,2-
disubstituted olefins bearing different electronic and steric
attributes. Investigations shed light on the nonradical nature of
the transformation, which proceeds through sequential
carbometalation followed by hydride transfer, consequently
expanding the scope to include substrates that are problematic
under previously established reaction conditions. The mech-
anistic principles derived from the present study are expected
to pave the way for new reaction design to tackle other
unresolved challenges in catalytic hydrofunctionalizations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03228.
■
sı
Experimental procedures and analytical data for all
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Hongyu Wang − Department of Chemistry, National
University of Singapore, Singapore 117544, Republic of
Singapore; Email: chmwho@nus.edu.sg
Ming Joo Koh − Department of Chemistry, National
University of Singapore, Singapore 117544, Republic of
Singapore; orcid.org/0000-0002-2534-4921;
Email: chmkmj@nus.edu.sg
a
Regioisomeric ratios (r.r.; branched:other isomers) and diastereo-
1
meric ratios were determined by GC and H NMR analysis. Yields
denote isolated yields. Conversions (based on disappearance of 1)
and 11:83 ratios were determined by GC analysis. See SI for details.
Authors
b
Chen-Fei Liu − Department of Chemistry, National University
of Singapore, Singapore 117544, Republic of Singapore
Xiaohua Luo − Department of Chemistry, National University
of Singapore, Singapore 117544, Republic of Singapore; Joint
School of National University of Singapore and Tianjin
University, International Campus of Tianjin University,
Binhai New City, Fuzhou 350207, China
Scheme 6. Proposed Ni-Catalyzed Mechanism for Alkene
Hydrocarbofunctionalization
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03228
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Ministry of Education of
Singapore Academic Research Fund Tier 1: R-143-000-B57-
114 (M.J.K.).
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